Naltrexone has reduced craving and relapse in some, but not all, alcoholics. One potential variable that[unreadable] might predict naltrexone, and potentially other opiate antagonist responses, is a difference in a single[unreadable] nucleotide substitution in the mu opiate receptor protein that makes that receptor respond differently to[unreadable] endogenous beta-endorphin as well as to exogenous opiate antagonists like naltrexone. An (A)denine to[unreadable] (G)uanine substitution at position 118 (A118G) in the coding region of the mu opiate receptor accounts for[unreadable] an asparagines (asn) to aspartate (asp) amino acid substitution at position 40 (asn40asp) in the receptor[unreadable] protein that occurs in about 15% of the population. The purpose of this1 proposal is to examine the role of[unreadable] this allelic difference in naltrexone responsivity in a well-established sub-acute dosing, brain imaging, and[unreadable] bar-lab paradigm. Interaction with another functional allele difference (va!158met substitution) in catechol-omethyl-[unreadable] transferase (COMT), an enzyme that controls CNS dopamine tone, will be explored.[unreadable] Three hundred non-treatment seeking alcoholics will be assessed and subtyped for mu opiate receptor[unreadable] and COMT allelic variants. Eighty individuals (40 with the more common AA gene and 40 with either an AG[unreadable] or GG gene) will be randomly assigned to take either naltrexone (50 mg/day) or a matching placebo for 7[unreadable] days. Val and Met alleles of the COMT gene will be equally distributed by urn randomization to all groups.[unreadable] After 5 days of natural drinking and one day of abstinence, subjects will undergo an alcohol cue-induced[unreadable] fMRI brain scan on day 6 of study drug. On day 7, after a standard alcohol drink, stimulation, sedation,[unreadable] intoxication, and craving will be evaluated over 40 minutes. Then subjects may choose to drink up to 8 minidrinks[unreadable] over a 2-hour period.[unreadable] It is hypothesized that when taking naltrexone, AG/GG (40asp) subjects compared to subjects with the[unreadable] AA (40asn) will show a greater reduction of cue-induced brain stimulation in the nucleus accumbens, less[unreadable] alcohol induced stimulation, and less free choice drinking. Those with both the asn40asp and val158met[unreadable] substitutions could have the strongest responses to naltrexone. This data will provide support for the use of[unreadable] genotyping in predicting which treatment seeking alcoholic will or will not respond to naltrexone. Also, this[unreadable] work brings pharmacogenetics to our Center for future medication/gene interaction studies.[unreadable]